Being responsible for over five million deaths every year, tobacco smoking is a chronic and deteriorating syndrome that represents one of the most severe health threats in Western countries. A recent analysis (Syed and Chaudhari, Nature Rev. Drug Discovery, 2013; 12: 97-98) estimates that there are over 1.3 billion smokers worldwide, placing the prevalence of tobacco addiction in adult population around 33%. While it is the enduring exposure to the many harmful substances contained in cigarette smoke that eventually leads to cardiovascular conditions, lung diseases, cancer, and other disorders, tobacco addiction is caused by nicotine. Nicotine is a psychoactive alkaloid that exerts its action increasing the level of dopamine in the mesolimbocortical system, a specific brain circuit strictly connected to reward, motivated behavior, and cue- and stress-induced drug craving (Caponnetto et al., Curr. Opin. Pharmacol., 2012; 12: 229-237). More in details, nicotine is an agonist of central nicotinic acetylcholine receptors (nAChRs). Upon binding, it increases the firing rate of the dopamine neurons that from the ventral tegmental area project toward the nucleus accumbens. Nicotine dependence is a very strong form of addiction, with the majority of smokers that attempt to quit relapsing within one month.
There are several medications approved by regulatory authorities for the treatment of nicotine addiction: i) nicotine replacement products, ii) Varenicline, an antagonist of the α4β2 nicotinic receptor, and iii) Buproprion, a non-tricyclic antidepressant. Nicotine vaccines based on active and passive immunization strategies are currently being in clinical development. Currently available treatments have shown promising effects in attenuating the symptoms of nicotine withdrawal but their success in preventing relapse and maintain long-term abstinence from nicotine has been only marginal (Benowitz, Annu. Rev. Pharmacol. Toxicol., 2009; 49: 57-71). It is important to note that a statistically significant co-morbidity between nicotine addiction, post-traumatic stress disorder (PTSD), and depression proneness has been consistently reported. For example, among combat veterans affected by PTSD, nicotine addiction was positively related to PTSD symptoms (Thorndike, Addict Behav., 2006; 31: 223-231). Smokers with PTSD are significantly more likely to be heavy smokers, i.e., those who smoke more than 25 cigarettes daily. Sustained release of bupropion has been shown to be effective for a short term smoking cessation in studies involving veterans with diagnosed PTSD and other concomitant psychiatric conditions (Hertzberg, J. Clin. Psychopharmacol., 2001; 21: 91-98).
D3 dopamine receptor (D3DR) is a molecular target that has been intensively investigated for the development of novel and efficient medications for the treatment of nicotine addiction (Le Foll et al., Expert Op. Invest. Drugs, 2007; 16: 45-57). In fact, this receptor subtype is mainly expressed in the mesolimbocortical system. In preclinical animal models, D3DR modulators were able to decrease the compulsion for nicotine self-administration under reinforcement schedules and prevented the establishment of Pavlovian drug-seeking behaviors. This suggests a translational strategy in which D3DR modulators could be used to attenuate the effects of drug-associated stimuli that eventually lead to the reinstatement of drug-seeking patterns. However, D3DR modulators did not display significant effects on nicotine intrinsic action and only had moderate effects on withdrawal.
Recently, behavioral and neurochemical evidences have established that the inhibition of the fatty acid amide hydrolase (FAAH) enzyme is effective in counteracting the abuse-related effects of nicotine. FAAH enzyme is a membrane bound serine hydrolase, member of the amidase signature family, characterized by an unusual Ser-Ser-Lys catalytic triad. FAAH catalyzes the degradation of several fatty acid N-acyl ethanolamides (FAEs), endogenous ligands for both cannabinoid (CB) receptors and nuclear peroxisome-proliferator activated receptors (PPAR) (Panlilio et al., Pharmacol. Ther., 2013; 138: 84-102). Selective FAAH enzyme inhibitors were able to reduce the nicotine-induced elevation of dopamine in the mesolimbocortical system, preventing the acquisition of nicotine self-administration and nicotine-induced preferential behaviors. These inhibitors acted elevating the levels of oleoylethanolamide (IDEA) and palmitoylethanolamide (PEA), endogenous agonists of nuclear receptor PPAR-alpha. Activation of PPAR-alpha increases the activity of several tyrosine kinases, which, in turn, blocks the downstream signaling initiated by nicotine binding to nAChRs (Mascia et al., Biol. Psychiatry, 2011; 69: 633-641). Moreover, blocking the cleavage of anandamide, FAAH enzyme inhibition has also been associated with an anxiolytic effect, which counteracts withdrawal symptoms and substance- and cue-induced relapse (Justinova et al., Biol. Psychiatry, 2008; 64: 930-937).
In this scenario, it is possible to envision treatment strategies that address both nicotine-craving symptoms and relapse by combining an inhibitor of the FAAH enzyme with a D3 receptor modulator. Moreover, this combination turns out to be beneficial for the treatment of other comorbid conditions often associated with nicotine addiction such as the already mentioned PTSD, as well as anxiety, pathological behaviours, and schizophrenia (Wu et al., J. Clin. Psychopharmacol., 2013; 33: 319-28). In case of schizophrenia, the combination of an inhibitor of the FAAH enzyme with a D3 receptor modulator could cause in specific brain areas a rise in the anandamide levels, which have been shown to negatively correlate with psychotic symptoms, pointing toward a protective role for anandamide (Leweke et al., Translational Psychiatry, 2012; 2: e94) and, at the same time, engage dopamine D3 improving cognitive function, emotional processing, executive function, flexibility, and social behavior, as demonstrated by in vivo experiments in animal models (Gross and Dresker, Handb. Exp. Pharmacol., 2012; 213: 167-210).
However, this combination therapy, presents some drawbacks. In addition to face the cumbersome administration of two separate drugs, which is something that generally hampers compliance, especially in patients diagnosed with psychotic symptoms, different pharmacokinetics of the respective drugs can impact on different pharmacodynamics. In practice, the clinician should face and manage a combination therapy with two different ADME curves (Absorption Distribution Metabolism Excretion). An innovative alternative to drug combinations are drugs that can hit multiple targets the so-called multi-target directed ligands (MTDLs; Cavalli et al. J. Med. Chem., 2008; 51:347-72). The strategy of targeting two or more proteins at the same time with a single compound can provide therapeutic effects superior to those of a selective drug (Zimmermann et al., Drug Discovery Today, 2007; 12: 34-42; Morphy R. and Rankovic Z. Drug Discovery Today, 2007, 12, 156-60; Hopkins A. L., Nat. Chem. Biol., 2008; 4: 682-90). This can be explained by the number of potential benefits offered by the use of MTDLs over cocktails or multicomponent drugs. The advantages of MTDLs can be summarized as follows: 1) reduced uncertainty in clinical development since predicting the pharmacokinetics of a single compound is much easier than with a drug cocktail, overcoming the problem of different bioavailability, pharmacokinetics and metabolism; 2) certainty on the pharmacodynamics; 3) improved effect of simultaneously inhibiting multiple targets; 4) improved safety by decreasing the side effects related to the load of a drug cocktail (reduced risk of drug-drug interactions); this is particularly relevant for drug metabolism, where the competition of different drugs for the same metabolic enzyme affect their toxicity. Another important advantage is a simplified therapeutic regimen and improved compliance, which is particularly important for patients that might experience relapse.
The MTDLs strategy is an innovative approach to the development of a centrally acting novel drug for the treatment of complex disorders, especially in view of the fact that the major basic processes that eventually lead to dependence are multi-factorial in nature (Gardner et al., Adv. Psychosom. Med., 2011; 30: 22-60). Such a strategy is based on the concept that a single multifunctional compound can be administered to hit multiple targets that cooperate in establishing and sustaining nicotine addiction, and therefore would prevent unwanted compensation among interacting pathways. Indeed, MTDLs could represent a practical alternative to the use of drug combinations. Since many substances of abuse share the basic mechanisms that induce addiction, such MTDLs may also be used as medications for other conditions that would clinically benefit from the combined inhibition of the fatty acid amide hydrolase enzyme and modulation of the D3 dopamine receptor.
One problem associated to MTDLs is that many of them have low efficiency in terms of their binding energy per unit of molecular weight. This is because they contain groups that are only important for one of the targets, being merely tolerated by the others. This results in an unbalanced profile (Morphy R. et al., Drug Discov. Today, 2007; 12: 156-160; Morphy R., J. Med. Chem., 2006; 4: 2969-2978). The way to fuse in a single molecule two pharmacophore elements, one distinctive of the FAAH molecular target and the other able to recognize the second molecular target (D3DR) is not obvious, as well as not obvious is the required optimization of both activities.
The inventors have solved this problem and unexpectedly found a class of compounds that is able to simultaneously inhibit the FAAH enzyme and modulate the D3D receptor, thus offering a superior medication to treat syndromes associated to the dependence and addiction to nicotine and other drugs of abuse.